Interferon-free hepatitis C treatment increases a surrogate of atherosclerotic cardiovascular disease risk in Black veterans living with HIV.

Veterans living with HIV (VLWH) and hepatitis C virus (HCV) co-infection have an exacerbated risk of cardiovascular disease (CVD). It is unknown if HCV cure reduces CVD risk in this population. We evaluated changes in low-density lipoprotein (LDL), as a surrogate of CVD risk, 18 months after HCV cure in VLWH. We found significant increases in LDL in VLWH with advanced fibrosis, potentially increasing CVD risk. Lower LDL thresholds to initiate lipid-lowering therapies in VLWH after HCV cure may be warranted.

Use of a machine learning model to predict retention in care in an urban HIV clinic.

Identifying barriers to retention in care (RIC) is critical to ending the HIV epidemic in the United States. Therefore, we developed a machine learning model (MLM) to identify predictive factors for RIC in an urban HIV clinic. Our MLM yielded a positive predictive value of 84%, higher than previously reported MLMs. We found that MLM can be used to develop interventional strategies to enhance RIC in HIV care.

CD38: an ecto-enzyme with functional diversity in T cells.

CD38, a nicotinamide adenine dinucleotide (NAD)+ glycohydrolase, is considered an activation marker of T lymphocytes in humans that is highly expressed during certain chronic viral infections. T cells constitute a heterogeneous population; however, the expression and function of CD38 has been poorly defined in distinct T cell compartments. We investigated the expression and function of CD38 in naïve and effector T cell subsets in the peripheral blood mononuclear cells (PBMCs) from healthy donors and people with HIV (PWH) using flow cytometry. Further, we examined the impact of CD38 expression on intracellular NAD+ levels, mitochondrial function, and intracellular cytokine production in response to virus-specific peptide stimulation (HIV Group specific antigen; Gag). Naïve T cells from healthy donors showed remarkably higher levels of CD38 expression than those of effector cells with concomitant reduced intracellular NAD+ levels, decreased mitochondrial membrane potential and lower metabolic activity. Blockade of CD38 by a small molecule inhibitor, 78c, increased metabolic function, mitochondrial mass and mitochondrial membrane potential in the naïve T lymphocytes. PWH exhibited similar frequencies of CD38+ cells in the T cell subsets. However, CD38 expression increased on Gag-specific IFN-γ and TNF-α producing cell compartments among effector T cells. 78c treatment resulted in reduced cytokine production, indicating its distinct expression and functional profile in different T cell subsets. In summary, in naïve cells high CD38 expression reflects lower metabolic activity, while in effector cells it preferentially contributes to immunopathogenesis by increasing inflammatory cytokine production. Thus, CD38 may be considered as a therapeutic target in chronic viral infections to reduce ongoing immune activation.

Viral hepatitis elimination challenges in low- and middle-income countries-Uzbekistan Hepatitis Elimination Program (UHEP).

BACKGROUND & AIMS: Chronic infection with hepatitis B and C viruses (HBV & HCV) is a major contributor to liver disease and liver-related mortality in Uzbekistan. There is a need to demonstrate the feasibility of large-scale simplified testing and treatment to implement a national viral hepatitis elimination program. METHODS: Thirteen polyclinics were utilized to screen, conduct follow-up biochemical measures and treat chronic HBV and HCV infection in the general adult population. Task shifting and motivational interviewing training allowed nurses to provide rapid screening and general practitioners (GPs) to treat individuals on-site. An electronic medical system tracked individuals through the cascade of care. RESULTS: The use of rapid tests allowed for screening of 60 769 people for HCV and HBV over 6 months and permitted outdoor testing during the COVID-19 pandemic along with COVID testing. 13%-14% of individuals were lost to follow-up after the rapid test, and another 62%-66% failed to come in for their consultation. One stop testing and treatment did not result in a statistically increase in retention and lack of patient awareness of viral hepatitis was identified as a key factor. Despite training, there were large differences between GPs and patients initiating treatment. CONCLUSIONS: The current study demonstrated the feasibility of large-scale general population screening and task shifting in low- and middle-income countries. However, such programs need to be proceeded by awareness campaign to minimize loss to follow up. In addition, multiple trainings are needed for GPs to bolster their skills to talk to patients about treatment.

The influence of inflammation on cardiovascular disease in women.

The onset of cardiovascular disease in women is almost a decade later than men, partly due to the protective effect of estrogen prior to menopause. Recently, it was noted that while there have been advances in improving the morbidity and mortality from CVD in women older than 55 years, the improvement in younger women has been stagnant. The mechanism behind this lag is unclear. This manuscript reviews the literature available on the sex-specific inflammatory response in the context of traditional and non-traditional cardiovascular disease risk factors. Our review suggests that women have a differential inflammatory response to various disease states that increases their risk for CVD and warrants a distinct prioritization from men when calculating cardiovascular disease risk.

Immunomodulatory therapies for COVID-19.

Purpose: As COVID-19 disease progresses, the host inflammatory response contributes to hypoxemia and severe and critical illness. In these latter stages of disease, patients may benefit from immunomodulatory therapies to control the aberrant host inflammatory response. In this review, we provide an overview of these therapies and provide summaries of the studies that led to issuance of FDA Emergency Use Authorization or recommendation by the Infectious Diseases Society of America (IDSA). Materials and methods: We reviewed English-language studies, Emergency Use Authorizations (EUAs), and guidelines from March 2020 to present. Conclusion and relevance: There are several therapies with proposed benefit in severe and critical COVID-19 disease. Few have been issued FDA EUA or recommendation by the Infectious Diseases Society of America (IDSA). Physicians should be familiar with the evidence supporting use of these therapies and the patient populations most likely to benefit from each.

Persistent CD38 Expression on CD8 + T Lymphocytes Contributes to Altered Mitochondrial Function and Chronic Inflammation in People With HIV, Despite ART.

BACKGROUND: Age-associated comorbidities are higher in people with HIV (PWH) than HIV-negative individuals. This is partially attributed to immune activation and CD38 expression on T cells driving chronic inflammation. However, the exact contribution of CD38-expressing T cells on the proinflammatory response is not completely understood. METHODS: CD38-expressing CD8 + T lymphocytes were measured from PWH and HIV-negative individuals. Mitochondrial mass, superoxide content, membrane depolarization of CD4 + and CD8 + T lymphocytes, and cytokine production after HIV(Gag)-specific peptide stimulation from CD38 + CD8 + T lymphocytes of PWH were measured to link biological effects of CD38 expression on cellular metabolism. RESULTS: The frequency of activated CD8 + CD38 + T cells persists in PWH on ART compared with HIV-negative individuals. Higher CD38 expression is associated with mitochondrial biogenesis and HIV(Gag)-specific proinflammatory cytokine production in PWH. Blockade of CD38 results in lower Gag-specific cytokine production. CONCLUSIONS: ART only partially reduced HIV-induced CD38 expression on CD8 + T cells. CD8 + CD38 + T cells are highly activated in vivo, and HIV-specific stimulation in vitro augments CD38 expression, contributing to a proinflammatory response despite virologic control with ART. Therefore, CD38 is a potential therapeutic target for mitigating chronic inflammation that likely drives cellular aging, comorbidities, and end-organ disease in PWH.

Predictors of in-hospital mortality in a cohort of people living with HIV (PLHIV) admitted to an academic medical intensive care unit from 2009 to 2014: A retrospective cohort study.

Outcomes for critically ill people living with human immunodeficiency virus (PLHIV) have changed with the use of antiretroviral therapy (ART). To identify these outcomes and correlates of mortality in a contemporary critically ill cohort in an urban academic medical center in Baltimore, a city with a high burden of HIV, we conducted a retrospective cohort study of individuals admitted to a medical intensive care unit (MICU) at a tertiary care center between 2009 and 2014. PLHIV who were at least 18 years of age with an index MICU admission of ≥24 hours during the 5-year study period were included in this analysis. Data were obtained for participants from the time of MICU admission until hospital discharge and up to 180 days after MICU admission. Logistic regression was used to identify independent predictors of hospital mortality. Between June 2009 and June 2014, 318 PLHIV admitted to the MICU met inclusion criteria. Eighty-six percent of the patients were non-Hispanic Blacks. Poorly controlled HIV was very common with 70.2% of patients having a CD4 cell count <200 cells/mm3 within 3 months prior to admission and only 34% of patients having an undetectable HIV viral load. Hospital mortality for the cohort was 17%. In a univariate model, mortality did not differ by demographic variables, CD4 cell count, HIV viral load, or ART use. Regression analysis adjusted by relevant covariates revealed that MICU patients admitted from the hospital ward were 6.4 times more likely to die in hospital than those admitted from emergency department. Other positive predictors were a diagnosis of end-stage liver disease, cardiac arrest, ventilator-dependent respiratory failure, vasopressor requirement, non-Hodgkin lymphoma, and symptomatic cytomegalovirus disease. In conclusion, in this critically ill cohort with HIV infection, most predictors of mortality were not directly related to HIV and were similar to those for the general population.

The Impact of Neocolonialism on India's COVID-19 Response.

In this paper, we analyze the impact of COVID-19 in India and the nation's shortcomings in responding appropriately to the pandemic. We discuss how international vaccine inequities, rooted in neocolonialism, and the WHO's broad recommendation of Global North pandemic responses (i.e., lockdowns, nonspecific social distancing) blunted the effectiveness of India's COVID-19 response and instead heightened classism, economic turmoil, and unnecessary infection and death from the virus.

Suboptimal Uptake, Retention, and Adherence of Daily Oral Prexposure Prophylaxis Among People With Opioid Use Disorder Receiving Hepatitis C Virus Treatment.

BACKGROUND: Daily oral preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) prevents human immunodeficiency (HIV) among people who inject drugs (PWID). Despite rising HIV incidence and injection drug use (IDU), PrEP use remains low and there is limited research about uptake, adherence, and retention among PWID. METHODS: The ANCHOR investigation evaluated a community-based care model collocating hepatitis C virus (HCV) treatment, medication for opioid use disorder (OUD), and PrEP in individuals in Washington, DC, and Baltimore, Maryland. PrEP counseling was conducted from HCV treatment day 0 until week 24. Subjects could start any time during this window, were followed for 48 weeks, and were assessed for adherence by self-report and dried blood spot TDF analysis. RESULTS: One hundred ninety-eight participants were enrolled, of whom 185 (93%) were HIV negative. Twenty-nine individuals (15.7% of HIV-negative cohort) initiated PrEP. One hundred sixteen participants (62.7%) met 2014 Centers for Disease Control and Prevention (CDC) PrEP criteria due to IDU (82 [44.3%]), sex (9 [4.9%]), or both practices (25 [13.5%]). Providers recommended PrEP to 94 individuals (50.8%), and recommendation was associated with PrEP uptake. Median treatment duration was 104 days (interquartile range, 28-276 days), with 8 participants retained through week 48. Adherence was variable over time by self-report and declined by TDF analysis. No HIV seroconversions occurred. CONCLUSIONS: This cohort of people with HCV and OUD experienced low uptake of PrEP despite the majority meeting CDC criteria. High rates of disruption and discontinuation, compounded by variable adherence, made TDF/FTC a suboptimal prevention strategy. Emerging modalities like long-acting formulations may address these barriers, but PWID have been excluded from their development to date.

Initiation of Low-threshold Buprenorphine in Nontreatment Seeking Patients With Opioid Use Disorder Engaged in Hepatitis C Treatment.

OBJECTIVE: The ANCHOR program offered buprenorphine treatment to people who inject drugs engaged in hepatitis C (HCV) treatment at a Washington, DC harm reduction organization. This analysis describes the program model and outcomes of the opioid care continuum at 1 year. METHODS: Primary outcomes were initiation of buprenorphine and retention in care, defined by an active buprenorphine prescription at given time points. Secondary outcomes included treatment interruptions, reasons for treatment noninitiation and termination, buprenorphine and opiate use, and HIV risk behaviors. Buprenorphine and opiate use were measured by urine toxicology screens and HIV risk behavior was quantified using a validated survey. RESULTS: Of 67 patients receiving HCV treatment not on opioid agonist therapy at baseline, 96% (n = 64) were interested and 73% (n = 49) initiated buprenorphine. Retention was 82% (n = 40), 65% (n = 32), and 59% (n = 29) at months 1, 6, and 12, respectively. Retention at 12 months was associated with self-reported engagement in routine medical care (P < 0.01), but was not associated with gender, stable housing, past opioid agonist therapy, or past overdose. Among retained patients, urine screens positive for opioids were 73% (n = 29), 56% (n = 18), and 79% (n = 23) at months 1, 6, and 12. There was a significant mean decrease in HIV risk-taking behavior scores over the treatment period, primarily driven by reduced injection frequency. CONCLUSIONS: Patients engaged in HCV treatment at a harm reduction organization showed a high rate of initiation of buprenorphine treatment, with retention comparable to other treatment settings. Although most patients continued using opioids on treatment, there was a reduced frequency of injection drug use, a significant driver of OUD-related risk. These data support the use of low-threshold buprenorphine access alongside HCV treatment to reduce morbidity and mortality in people with OUD.

Evaluation of the Efficacy and Safety of Rheum rhaponticum Root Extract (ERr 731) for Menopausal Symptoms in Perimenopausal Indian Women: An Interim Analysis.

BACKGROUND: Hormonal therapy for menopause has been found to be the most efficacious treatment, but it may be associated with adverse effects in some of the women. Rheum rhaponticum root extract ("ERr 731"), which is available worldwide, is a natural, reliable, effective, and well-tolerated remedy for women in perimenopausal women with menopausal symptoms (MSs), but there is no Indian study demonstrating its efficacy, safety, and tolerability till date. OBJECTIVE: This study aimed to evaluate the efficacy and safety of ERr 731 in alleviating MSs in perimenopausal Indian women. PATIENTS AND METHODS: In this open-labeled prospective study, 129 perimenopausal women were treated with tablet containing 4 mg of Rr dried root extract once daily for 12 weeks. The Menopause Rating Scale (MRS) II score, endometrial thickness (ET), blood pressure, glycemic status, lipid profile, and high-sensitivity C-reactive protein (hs-CRP) level were periodically assessed and compared. RESULTS: A significant reduction (67% by 12th week) in the mean MRS II score was observed from baseline till the end of 12 weeks (18.1; 95% confidence interval [CI]: 17.0-19.2; P < 0.001). A monotonic reduction in the mean total MRS II score over time was found (1.51 units/week; 95% CI: 1.42-1.60 units/week; P < 0.001) noticeable. There was a reduction in the mean ET from baseline till the end of 12 weeks, although the change was not significant. There were significant reductions in the mean fasting (6.3 mg/dl; 95% CI: 1.7-11.0 mg/dl; P = 0.008) and postprandial (6.3 mg/dl; 95% CI: 1.0-11.7; P = 0.021) blood glucose levels and glycated hemoglobin level (0.30%; 95% CI: 0.085-0.520; P = 0.007) at 12 weeks. No significant changes were noted in terms of blood pressure, lipid profile, and hs-CRP level. The drug was found to be safe. CONCLUSION: ERr 731 was well tolerated and was found to be efficacious and safe in alleviating MSs in Indian perimenopausal women.

Oral Polio Vaccine to Protect Against COVID-19: Out of the Box Strategies?

The global coronavirus disease 2019 pandemic has raised significant concerns of developing rapid, broad strategies to protect the vulnerable population and prevent morbidity and mortality. However, even with an aggressive approach, controlling the pandemic has been challenging, with concerns of emerging variants that likely escape vaccines, nonadherence of social distancing/preventive measures by the public, and challenges in rapid implementation of a global vaccination program that involves mass production, distribution, and execution. In this review, we revisit the utilization of attenuated vaccinations, such as the oral polio vaccine, which are safe, easy to administer, and likely provide cross-protection against respiratory pathogens. We discuss the rationale and data supporting its use and detail description of available vaccines that could be repurposed for curtailing the pandemic.

Hepatitis C Virus Infection in Persons Who Inject Drugs in the Middle East and North Africa: Intervention Strategies.

There is a high incidence and prevalence of hepatitis C viral infection in persons with or without substance use disorders (SUDs) in the Middle East and North Africa (MENA) region, but only a small number receive comprehensive care. Highly effective direct-acting antiviral (DAA) medications are available at substantially lower costs; however, complete elimination of the hepatitis C virus (HCV) can only be achieved if integrated care strategies target those at highest risk for HCV infection and transmission and improve access to care. Due to the high prevalence of SUD in the MENA region, strategies to eliminate HCV must focus on integrated healthcare across multiple subspecialties, including addiction medicine, psychiatry, infectious diseases, hepatology, and social work. In this invited manuscript, we review the epidemiology of HCV in the MENA region and highlight intervention strategies to attain the WHO's goal of HCV eradication by 2030.

Global prevalence of hepatitis C virus in women of childbearing age in 2019: a modelling study.

BACKGROUND: Treatment for infection with hepatitis C virus (HCV) during pregnancy has not yet been approved; however, interventions specifically targeting women, especially those of childbearing age (15-49 years), could prevent vertical transmission and community spread. To assess the impact of such interventions, improved prevalence estimates in this group are needed. We aimed to estimate the global prevalence of viraemic HCV in 2019 among women of childbearing age. METHODS: In this modelling study, we used previously developed models for 110 countries inputted with country-specific demographic and HCV epidemiology data. We did a literature review, searching PubMed, Embase, and grey literature for studies published between Jan 1, 2000, and June 30, 2018, reporting HCV antibody or viraemic prevalence in women of childbearing age. Studies from the literature review and studies in models were compared by use of a data quality scoring system and models were updated, as appropriate, when a better study was identified. We used these HCV disease burden models to calculate the 2019 prevalence of viraemic HCV in women of childbearing age. In countries without a model, prevalence was extrapolated by Global Burden of Disease (GBD) region. FINDINGS: An estimated 14 860 000 (95% uncertainty interval [UI] 9 667 000-18 282 000) women aged 15-49 years had HCV infection worldwide in 2019, corresponding to a viraemic prevalence of 0·78% (95% UI 0·62-0·86). Globally, HCV prevalence increased with age, rising from 0·25% (95% UI 0·20-0·27) in women aged 15-19 years to 1·21% (0·97-1·34) in women aged 45-49 years. China (16% of total infections) and Pakistan (15%) had the greatest numbers of viraemic infections, but viraemic prevalence was highest in Mongolia (5·14%, 95% CI 3·46-6·28) and Burundi (4·91%, 3·80-18·75). Of the countries with 500 cases or more, viraemic prevalence was lowest in Chile (0·07%, 95% UI 0·04-0·12). Among the GBD regions, eastern Europe had the highest viraemic prevalence (3·39%, 95% UI 1·88-3·54). By WHO region, the Eastern Mediterranean region had the highest viraemic prevalence (1·75%, 95% UI 1·26- 1·90). INTERPRETATION: Most research on HCV disease burden among women aged 15-49 years focuses on pregnant women. Using modelling, this analysis provides global and national estimates of HCV prevalence in all women of childbearing age. These data can inform preconception test-and-treat strategies to reduce vertical transmission and total disease burden. FUNDING: Gilead Sciences, John C Martin Foundation, private donors.

Duration of posaconazole therapy for Aspergillus fumigatus osteomyelitis dictated by serial monitoring of 1,3-beta-D glucan.

Here, we present a case of an immunocompetent 37-year old male who developed Aspergillus fumigatus osteomyelitis 16 years after extensive chest wall reconstructive surgery for Ewing sarcoma. His treatment course was complicated by a severe adverse drug reaction to voriconazole, requiring the use of oral posaconazole therapy. Serum 1,3-beta-D glucan assay was utilized to dictate the duration of posaconazole therapy. The patient successfully completed 9 months of oral posaconazole therapy and has not had clinical recurrence for 9 months off antifungal therapy.

The Effect of GS-548351 on the Pharmacokinetics of Midazolam Following Multiple Doses of ANS-6637 in Healthy Adults.

ANS-6637, a pro-drug of GS-548351, is a selective, reversible inhibitor of aldehyde dehydrogenase isoform 2 under development as an anticraving agent for the treatment of substance use disorders. In vitro testing indicates that GS-548351 is an inhibitor and inducer of cytochrome P450 family 3, subfamily A (CYP3A). In this phase 1 single-center, open-label, fixed-sequence drug-drug interaction study we assessed the impact of steady-state GS-548351 on single-dose pharmacokinetics of midazolam, an index substrate for CYP3A. Twelve healthy volunteers received 600 mg of ANS-6637 by mouth daily from study days 3 to 8 and a single 5-mg oral dose of midazolam on days 1 and 8. Pharmacokinetic samples were collected over 24 hours on days 1 and 8, then analyzed using liquid chromatography-tandem mass spectrometry. The prespecified no-effect range for the 90% confidence interval (CI) of the geometric mean ratio (GMR) of midazolam coadministered with ANS-6637 (day 8) compared with midazolam alone (day 1) was 0.7-1.43. There was an increase in midazolam AUC0-∞ (GMR [90%CI]) that was within the no-effect range (1.26 [1.12-1.425]) and an increase in midazolam Cmax that was outside the range (1.22 [1.03-1.45]). The AUC0-∞ (1.08 [0.91-1.27]) and Cmax (0.95 [0.75-1.2]) of 1-hydroxymidazolam, the primary metabolite of midazolam, were also within the no-effect range. A single grade 3 adverse event (alanine aminotransferase elevation) was identified and resolved following discontinuation of the study drug. Overall, multidose ANS-6637 was well tolerated and did not alter the PK of midazolam beyond a small increase in AUC0-∞ that is unlikely to be clinically significant.